Citations

Abstract The recent development of imaging and sequencing technologies enables systematic advances in the clinical study of lung cancer. Meanwhile, the human mind is limited in effectively handling and fully utilizing the accumulation of such enormous amounts of data. Machine learning-based approaches play a critical role in integrating and analyzing these large and complex datasets, which have extensively characterized lung cancer through the use of different perspectives from these accrued data. In this review, we provide an overview of machine learning-based approaches that strengthen the varying aspects of lung cancer diagnosis and therapy, including early detection, auxiliary diagnosis, prognosis prediction, and immunotherapy practice. Moreover, we highlight the challenges and opportunities for future applications of machine learning in lung cancer.

Introduction: The voltage-gated proton channel Hv1 is a member of the voltage-gated ion channel family. Hv1 channel controls acid extrusion and regulates pH homeostasis in various cell types. Recent evidence showed that the Hv1 were expressed in the heart. Hypothesis: We propose the Hv1 channel is associated with cardiac function. Methods: To investigate the role of Hv1 in cardiac myocytes, we performed a transcriptomic analysis of wild-type (WT) and Hv1-/- mouse hearts. Results: Hv1 null hearts exhibited a differential transcriptome profile compared with wild-type hearts. The RNA-seq data indicating impaired pH homeostasis in Hv1 null hearts were the downregulated NADPH oxidoreductases (NOXs) and decreased expression of Cl-/HCO3- exchanger. Additionally, Hv1 null hearts exhibited differential expression of cardiac ion channels, suggesting a potential role of Hv1 in cardiac electrophysiological remodeling. Conclusions: The data indicated that Hv1 was involved in cardiac pH homeostasis and showed that Hv1 was a regulator of gene transcriptional networks controlling NOX signaling and CO2 homeostasis in the heart. The study highlights the importance of Hv1 in cardiac function and may present a new target associated with heart diseases.

Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

Abstract CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. CIViC contains peer-reviewed, published literature curated and expertly-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC’s functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new Evidence Types (Predisposing, Oncogenic and Functional). The growing CIViC knowledgebase has over 300 contributors and distributes clinically-relevant cancer variant data currently representing >3200 variants in >470 genes from >3100 publications.

Peripheral arterial and venous examinations are performed regularly in vascular labs and interpreted by physicians of different specialities. Many vascular examinations have nonvascular pathology that is either inadvertently imaged by the sonographer or imaged with intent as it relates to patient's symptoms. It is prudent for every reader of vascular studies to be acquainted with the sonographic appearance of these non‐vascular lesions to enable appropriate and optimal interpretation that has a direct bearing on patient's clinical care. Our review includes a discussion of the nonvascular pathologies like lymph nodes, soft tissue edema, soft tissue fluid collections, musculotendinous injuries, soft tissue masses, and joint and bursal pathologies that may be encountered during interpretation of vascular exams. The pictorial essay includes a discussion of their sonographic appearances and pitfalls in interpretation. Multiple illustrative examples and sonographic images of the non‐vascular pathologies found during interpretation of vascular studies have been utilized to highlight their appearances.

Abstract Background: As a key receptor tyrosine kinase (RTK) regulating tumorigenesis, AXL is overexpressed in multiple different types of cancers. AXL can be activated by homodimerization after binding with its ligand, growth arrest specific 6 protein (Gas6) or by heterodimerization with other RTKs. AXL overexpression and/or activation have been reported to promote cancer cell proliferation, migration/invasion and to induce resistance to targeted therapy. However, the AXL downstream signaling network has not yet been fully elucidated. Methods: We employed a CRISPR-CAS9-based knockout technology to create AXL inducible knockout cells in a human triple negative breast cancer (TNBC) cell line, HCC1395. In order to explore the downstream signaling events driven by AXL, we induced AXL knockout for 72 hours and used a 6-plex TMT-labeling-based quantitative proteomic approach to characterize the protein phosphorylation alterations induced by AXL knockout. IMAC and anti-phosphotyrosine antibody (pY1000)-based phosphopeptide enrichment methods were used to comprehensively quantify the phosphoproteome changes induced by AXL knockout. Results: In this study, we identified 38,525 phospho serine/threonine sites and 1,427 phosphotyrosine sites. In response to AXL knockout, 1,581 phospho serine/threonine sites and 40 phosphotyrosine sites showed significant differences between AXL-KO and AXL-WT groups with >1.5-fold change and p<0.05 as the cutoff. Among them, 982 phosphoserine/threonine sites and 30 phosphotyrosine sites were decreased, while 599 phospho serine/threonine sites and 10 phosphotyrosine sites were increased in AXL-KO cells. Signaling pathway enrichment analysis revealed that suppressing AXL expression could inhibit multiple important cancer related signaling pathways, including cell cycle, focal adhesion, MAPK signaling pathway, p53 signaling pathway and mTOR signaling pathway. Conclusion: Quantitative analysis of the phosphoproteome driven by AXL demonstrated that AXL plays a pivotal role in regulating canonical oncogenic signaling but also signaling pathways involved in RNA processing and DNA repair. Our data also suggest that targeting AXL could suppress these oncogenic signaling pathways and have therapeutic potential to improve clinical outcomes for patients with AXL overexpression. Citation Format: Li Wang, Nicole Pearson, Yuning Xiong, Santosh Renuse, Ran Cheng, Jodi M. Carter, Akhilesh Pandey, Xinyan Wu. Quantitative phosphoproteomic analysis of AXL signaling network in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3913.

Abstract Bispecific T cell engagers (TCE) are novel immunotherapies for cancer that redirect a synthetic immune response against tumors. Early clinical trial data show that BCMA-targeting TCEs are highly effective immunotherapies for treating relapsed and refractory multiple myeloma (MM). Thus, it is important to define combinatorial approaches that increase the efficacy and durability of TCE. We recently investigated a murine anti-BCMA TCE in the immunocompetent IMiD-sensitive Vk*MYChCRBN model of MM. Our data show that anti-BCMA TCE was safe and efficacious in most mice, but failed in those with high-tumor burden, consistent with clinical reports of TCE in leukemia. We tested the combination of anti-BCMA TCE and IMiDs to provide an additive anti-tumor effect and stimulatory cytokines, such as IL-2 in the tumor environment. This combination expanded cytolytic T cells and improved activity even in IMiD-resistant high-tumor burden cases. Yet, survival was only marginally extended due to T cell exhaustion. We hypothesized that blockade of the inhibitory immune checkpoint PD-1 would synergize with TCE and IMiDs to potentiate the response directed by the TCE by reinvigorating exhausted T cells. We evaluated the efficacy of the triple therapy combination in Vk*MYChCRBN: the anti-BCMA TCE, pomalidomide, and anti-PD1. Checkpoint blockade alone, or in combination with TCE did not improve tumor control or survival compared to control treatments. The triple combination proved most effective at controlling tumor growth, inducing a complete response after 2 weeks of treatment, and was curative in 40% of the mice. Longitudinal analysis of the immune response showed that the addition of anti-PD1 to TCE-IMiDs rescued T cell expansion at tumor sites and sustained expression of activation markers after repeated doses. Longitudinal analysis of blood and bone marrow (BM) cytokines showed the typical profile associated with cytokine release syndrome (CRS) during T cell immunotherapy. Of note, we observed IL-2, IFN-γ, and GM-CSF production was sustained in the BM tumor environment in the triple combination. We suspect that these cytokines, especially IL-2, are key to sustaining non-exhausted effector T cell proliferation in response to TCE therapy. Expectedly, we observed toxicity with the elevated cytokine release in the triple combination. that we anticipate could be controlled with step-up dosing or CRS mitigation treatment. We conclude that combination of PD1 blockade, IMiDs and TCE provides superior efficacy in the immunocompetent preclinical model of MM, Vk*MYChCRBN, while increasing inflammatory pathways that can lead to CRS. Finally, as we found this combination to be curative in some mice, we will investigate whether this combination immunotherapy also enhanced an endogenous anti-tumor immune response leading to protective immunosurveillance. Citation Format: Erin W. Meermeier, Seth J. Welsh, Meaghen Sharik, Megan T. Du, Chang-Xin Shi, Bryant Chau, Feng Wang, Matthew Wheeler, Natalie Bezman, Pavel Strop, P. Leif Bergsagel, Marta Chesi. PD-1 blockade synergizes with IMiDs to enhance bispecific T cell engager immune responses to Vk*MYChCRBN multiple myeloma by preventing T cell exhaustion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5588.